Process for Production of Benzimidazole Derivative Salt Precipitate

ABSTRACT

The present invention provides a process for the production of a 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1 H-benzimidazole alkali metal salt (1), which is a drug or an intermediate for the production of a drug, the process not requiring large-scale equipment and being excellent in terms of workability, operability and energy conservation. According to the present invention, there is disclosed a process for the production of a salt precipitate represented by formula (1)  
                 
(wherein B represents an alkali metal ion), the process comprising the steps of: 
 
dissolving the compound represented by formula (2)  
                 
in a first organic solvent and adding an alkali metal hydroxide, or dissolving the alkali metal hydroxide in the first organic solvent and adding the compound represented by formula (2); and further adding a second organic solvent to a reaction mixture obtained.

TECHNICAL FIELD

The present invention relates to a process for the production of aprecipitate of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt that is useful as a drug such as a gastric acidsecretion inhibiting drug or an anti-ulcer drug, or an intermediate forthe production of such a drug.

BACKGROUND ART

It is known that2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salts have a gastric acid secretion inhibiting action andare thus useful as anti-ulcer drugs (see Patent Document 1: U.S. Pat.No. 5,045,552). Moreover, such a salt can be produced using any ofvarious processes, in particular a production process using a freezedrying method is known (see Patent Document 2: Japanese PatentApplication Laid-Open No. H7-278141, or Patent Document 3: InternationalPublication No. WO03/101452).

However, with the freeze drying method, large-scale equipment isrequired in actual production of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salts, and moreover the method cannot necessarily be saidto be excellent in terms of workability, operability and energyconservation.

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

It is thus is an object of the present invention to provide a processfor the production of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt that is useful as an anti-ulcer drug, the process notrequiring large-scale equipment and being excellent in terms ofworkability, operability and energy conservation.

Means for Solving the Problems

In view of the above circumstances, the present inventor has carried outstudies with vigor, and as a result have arrived at the presentinvention after discovering a process for the production of the salts asdescribed above, which attains the above object, i.e. does not requirelarge-scale equipment and is excellent in terms of workability,operability and energy conservation.

That is, the present invention provides:[1] a process for the production of a salt precipitate represented byformula (1)

(wherein B represents an alkali metal ion), i.e. a process for theproduction of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (1), the process comprising the steps of:

dissolving a compound represented by formula (2)

in a first organic solvent and adding an alkali metal hydroxide, ordissolving the alkali metal hydroxide in the first organic solvent andadding the compound represented by formula (2); and

further adding a second organic solvent to a reaction mixture obtained,

Advantageous Effects of the Invention

The present invention is a useful production process, in that a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (1) that is a drug or an intermediate for theproduction of a drug can be produced through a process that does notrequire large-scale equipment and is excellent in terms of workability,operability and energy conservation.

BEST MODE FOR CARRYING OUT THE INVENTION

The production process according to the present invention is a processfor the production of a salt precipitate represented by formula (1)

(wherein B represents an alkali metal ion), the production processcomprising the steps of:

dissolving a compound represented by formula (2)

in a first organic solvent and adding an alkali metal hydroxide, ordissolving the alkali metal hydroxide in the first organic solvent andadding the compound represented by formula (2); and

further adding a second organic solvent to the reaction mixtureobtained.

There are no particular limitations on the first organic solvent used inthe above process so long as the compound represented by formula (2)(hereinafter merely referred to as “compound (2)”) dissolves therein,but an alcohol such as methanol, ethanol, propanol, isopropanol, butanolor tert-butanol are preferable, methanol or ethanol being particularlypreferable.

There are no particular limitations on the second organic solvent usedin the above process so long as the salt represented by formula (1)(hereinafter merely referred to as “compound (1)” or “salt (1)”) doesnot readily dissolve therein, but an ether such as diethyl ether,diisopropyl ether, tert-butyl(methyl) ether, tetrahydrofuran, dioxane ordimethoxyethane are preferable, tert-butyl(methyl) ether or diisopropylether being particularly preferable.

The amount of the first organic solvent used in the above process isgenerally in a range of from 0.9 to 1.5 ml based on 1 g of compound (2).

The amount of the second organic solvent used in the above process isgenerally in a range of from 10 to 110 ml based on 1 g of compound (2).

Examples of the alkali metal hydroxide used in the above process includesodium hydroxide, potassium hydroxide or the like, sodium hydroxidebeing preferable.

There are no particular limitations on the amount of the alkali metalhydroxide used in the above process so long as the purity of compound(1) obtained as the precipitate is not markedly reduced, but this amountis preferably in a range of from 0.99 to 1 equivalents based on compound(2).

In the above process, there are no particular limitations on thetemperature when dissolving compound (2) in the first organic solvent orin the first organic solvent in which the alkali metal hydroxide hasbeen dissolved so long as this temperature is within a range such thatdecomposition of compound (2) or salt (1) does not occur, but thistemperature is generally in a range of from 0 to 30° C.

In the above process, there are no particular limitations on thetemperature when adding the alkali metal hydroxide to the solution ofcompound (2) in the first organic solvent so long as this temperature iswithin a range such that decomposition of compound (2) or salt (1) doesnot occur, but this temperature is generally in a range of from 0 to 30°C.

In the above process, the conversion from compound (2) to salt (1)generally takes place immediately.

In the above process, when adding the second organic solvent to thesolution of salt (1) in the first organic solvent, it is preferable toadd the second organic solvent not all at once, but rather continuouslyand gradually, or in divided amounts.

In the above process, the precipitate of salt (1) obtained refers toamorphous matter, crystalline matter, or a mixture thereof.

The precipitate of salt (1) obtained through the above process can beisolated by filtering off, and drying under reduced pressure or normalpressure. The isolated precipitate can be used for a desired preparationas is, or by milling it as appropriate.

The production process according to the present invention is preferably:

-   [2] the process according to above [1], wherein the first organic    solvent is an alcohol;-   [3] the process according to above [1] or [2], wherein the first    organic solvent is methanol or ethanol;-   [4] the process according to any one of above [1] to [3], wherein    the alkali metal hydroxide is sodium hydroxide, and B is a sodium    ion;-   [5] the process according to any one of above [1] to [4], wherein    the second organic solvent is an ether; or-   [6] the process according to any one of above [1] to [5], wherein    the second organic solvent is tert-butyl(methyl) ether or    diisopropyl ether.

In the production process of the present invention, compound (2) used asthe starting material can be produced using the process described inPatent Document 1 or a publicly known improvement of this process (e.g.Japanese Patent Application Publication No. H11-71370, Japanese PatentApplication Publication No. 2000-143659, International Publication No.WO01/68594, European Patent Application Publication No. EP 1,270,555,etc.). The compound (2) can also be produced through the followingprocess.

Note that the compound represented by formula (3) (hereinafter merelyreferred to as “compound (3)”; similar notation will also be used forthe compounds represented by formulae (4) and (5)), compound (4), andcompound (5) are all publicly known compounds.

First Step

This step is a step of producing compound (4) in a crude statecomprising reacting compound (3) with a chlorinating agent in an inertsolvent, and concentrating the reaction mixture obtained.

The present step differs from the process described in Patent Document 1in that the reaction mixture is merely concentrated, other work up notbeing carried out.

There are no particular limitations on the inert solvent used in thepresent step so long as the starting material compound can be dissolvedtherein to some extent and the solvent does not impede the reaction: forexample, aromatic hydrocarbons such as benzene, toluene or xylene;organic acid esters such as methyl acetate or ethyl acetate; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane ordimethoxyethane; or halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride or dichloroethane can be preferablyused, toluene, ethyl acetate, dimethoxyethane or dichloromethane beingparticularly preferably used.

As the chlorinating agent used in the present step, for examplephosphorous trichloride, phosphorus pentachloride, phosphorusoxychloride, thionyl chloride or the like can be used, but it ispreferable to use one such as thionyl chloride that can be removed bybeing distilled off with the solvent.

The reaction temperature in the present step varies depending on thesolvent, starting material compound, and chlorinating agent used and soon, but is generally in a range of from −20 to 50° C., preferably 0 to20° C.

The reaction time in the present step varies depending on the solvent,starting material compound, chlorinating agent, and reaction temperatureused and so on, but is generally in a range of from 30 minutes to 6hours, preferably 1 to 2 hours.

After completion of the reaction, the reaction mixture is concentratedand dried under reduced pressure or normal pressure, and can then beused in the second step as is without being purified in particular.

Second Step

This step is a step of producing compound (5) by reacting compound (4)obtained in the first step with 2-benzimidazolethiol in the presence ofa base in an inert solvent.

There are no particular limitations on the inert solvent used in thepresent step so long as the starting material compound can be dissolvedtherein to some extent and the solvent does not impede the reaction; forexample, alcohols such as methanol, ethanol, propanol, isopropanol,butanol or tert-butanol can be used, ethanol being particularlypreferably used.

There are no particular limitations on the base used in the present stepso long as the base dissolves in the solvent to some extent; forexample, an alkali metal hydride such as sodium hydroxide or potassiumhydroxide can be used, sodium hydroxide being particularly preferablyused.

The reaction temperature in the present step varies depending on thesolvent, starting material compound, and base used and so on, but isgenerally in a range of from −20 to 70° C., preferably 20 to 60° C.

The reaction time in the present step varies depending on the solvent,starting material compound, base, and reaction temperature used and soon, but is generally in a range of from 30 minutes to 6 hours,preferably 1 to 2 hours.

After completion of the reaction, compound (5) can be isolated from thereaction mixture according to the well-known method. For example, aftercompletion of the reaction, the reaction mixture is subjected to vacuumconcentration, then extraction is carried out using water and an organicsolvent immiscible with water (e.g. dichloromethane, ethyl acetate,etc.), the organic layer is washed using a sodium hydroxide aqueoussolution and water, and then concentration is carried out, wherebycompound (5) can be produced.

In particular, by using an organic solvent such as one of the following,highly purified compound (5) can be produced as crystals:

ethers such as diethyl ether, diisopropyl ether, tert-butyl(methyl)ether, tetrahydrofuran, dioxane or dimethoxyethane (particularlydiisopropyl ether or tert-butyl(methyl) ether);

nitriles such as acetonitrile (particularly acetonitrile);

aromatic hydrocarbons such as benzene, toluene or xylene (particularlytoluene);

alcohosl such as methanol, ethanol, propanol or isopropanol(particularly isopropanol);

ketones such as acetone or methyl ethyl ketone (particularly acetone);

organic acid esters such as methyl acetate, ethyl acetate, dimethylcarbonate or diethyl carbonate (particularly ethyl acetate or diethylcarbonate); or

mixed solvents comprising at least two of the above solvents.

In the crystallization, the amount of the solvent used varies dependingon the type of the solvent, but is in a range of from 3 to 40 ml basedon 1 g of compound (5).

Third Step

This step is a step of producing compound (2) by reacting compound (5)with an oxidizing agent in an inert solvent.

There are no particular limitations on the inert solvent used in thepresent step so long as the starting material compound can be dissolvedtherein to some extent and the solvent does not impede the reaction; forexample, halogenated hydrocarbons such as chloroform, dichloromethane,carbon tetrachloride or dichloroethane can be preferably used,dichloromethane being particularly preferably used.

As the oxidizing agent used in the present step, hydrogen peroxide,peracetic acid, m-chloroperbenzoic acid, sodium periodate or the likecan be used, it being preferable to use m-chloroperbenzoic acid.

If one equivalent of the oxidizing agent is used based on compound (5),then compounds produced through further oxidation of compound (2) areby-produced; the oxidizing agent is thus preferably used in an amountless than one equivalent, particularly preferably in a range of from 0.3to 0.6 equivalents.

The reaction temperature in the present step varies depending on thesolvent, starting material compound, and oxidizing agent used and so on,but is generally in a range of from −50 to 0° C., preferably −30 to −10°C.

The reaction time in the present step varies depending on the solvent,starting material compound, oxidizing agent, and reaction temperatureused and so on, but is generally in a range of from 30 minutes to 6hours, preferably 1 to 2 hours.

After completion of the reaction, compound (2) can be isolated from thereaction mixture according to the well-known method. For example, thefollowing operations are carried out in order:

operation 1: a basic aqueous solution (e.g. an aqueous solution of analkali metal hydroxide, particularly a sodium hydroxide aqueoussolution) is added to the reaction mixture obtained, the mixture isstrongly stirred or shaken and then left to stand, and then the organiclayer is separated off so as to obtain the aqueous layer (a);

operation 2: an organic solvent (e.g. halogenated hydrocarbons such aschloroform, dichloromethane, carbon tetrachloride or dichloroethane,particularly dichloromethane) is added to the aqueous layer (a), themixture is strongly stirred or shaken and then left to stand, and thenthe organic layer is separated off so as to obtain the aqueous layer(b);

operation 3: an aqueous buffer solution (e.g. an ammonium acetateaqueous solution) and the same organic solvent as before are added tothe aqueous layer (b), and with the pH in a range of from 10.0 to 10.5,the mixture is strongly stirred or shaken and then left to stand, andthen separation is carried out so as to obtain the organic layer (a) andthe aqueous layer (c);

operation 4: the same organic solvent as before is added to the aqueouslayer (c), the mixture is strongly stirred or shaken and then left tostand, and then separation is carried out so as to obtain the organiclayer (b), which is combined with the organic layer (a), and then wateror aqueous sodium bicarbonate solution is added, the mixture is stronglystirred or shaken and then left to stand, and then the aqueous layer isremoved and the organic layer (c) thus obtained is concentrated.

In particular, after the concentration, by carrying out crystallizationusing an organic solvent such as one of the following, highly purifiedcompound (2) can be produced as crystals:

ethers such as diethyl ether, diisopropyl ether, tert-butyl(methyl)ether, tetrahydrofuran, dioxane or dimethoxyethane (particularly diethylether);

nitriles such as acetonitrile (particularly acetonitrile);

aromatic hydrocarbons such as benzene, toluene or xylene (particularlytoluene);

alcohols such as methanol, ethanol, propanol, isopropanol or isobutanol(particularly isopropanol);

ketones such as acetone or methyl ethyl ketone (particularly acetone);

organic acid esters such as methyl acetate, ethyl acetate, dimethylcarbonate or diethyl carbonate (particularly ethyl acetate); or

mixed solvents of the above solvents, particularly ethers, nitrites,ketones or organic acid esters plus halogenated hydrocarbons such aschloroform, dichloromethane, carbon tetrachloride or dichloroethane(particularly acetonitrile plus dichloromethane, acetone plusdichloromethane, ethyl acetate plus dichloromethane, or diethyl etherplus dichloromethane).

The present invention will be described in more detail below, showingExamples and Reference Examples. Note, however, that the followingdescription is merely illustrative, the present invention not beinglimited thereto in any case.

The meanings of abbreviations used in the following are as follows:

mcpba: metachloroperbenzoic acid

TLC: thin layer chromatography

HPLC: high performance liquid chromatography

EXAMPLES Example 1

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(4.97 g (13.8 mmol)) was dissolved in methanol (5 ml). Sodium hydroxide(0.559 g (13.7 mmol)) was then put into the methanol solution, and afterdissolution had been confirmed, dipropyl ether (500 ml) was addedslowly, whereby2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt (4.77 g) was obtained through precipitation (yield 90.3%).

Example 2

Ethanol (30 ml) was added to sodium hydroxide (2.25 g (55.1 mmol)), anddissolution was carried out.2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(20.0 g (55.6 mmol)) was then put into the ethanol solution, and afterdissolution had been confirmed, diisopropyl ether (2000 ml) was addedslowly, whereby2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt (22.8 g) was obtained through precipitation (yield 100%).

Example 3

Ethanol (22.5 ml) was added to sodium hydroxide (1.65 g (41.3 mmol)),and dissolution was carried out.2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(15.0 g (41.7 mmol)) was then put into the ethanol solution, and afterdissolution had been confirmed, tert-butyl methyl ether (160 ml) wasadded slowly, whereby2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt (15.9 g) was obtained through precipitation (yield 100%).

Reference Example 1

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g(35.6 mmol)) was added dropwise into the solution in a temperature thatdid not exceed 25° C. Stirring was carried out at room temperature, andthen after it had been confirmed by TLC that the starting material haddisappeared, vacuum concentration was carried out, thus obtaining2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g (yield:97.3%)).

Reference Example 2

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride(4.23 g (35.6 mmol)) was added dropwise into the solution in atemperature that did not exceed 25° C. Stirring was carried out at roomtemperature, and then after it had been confirmed by TLC that thestarting material had disappeared, vacuum concentration was carried out,thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine(6.14 g (yield: 97.4%)).

Reference Example 3

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in dimethoxyethane (40 ml), and thionyl chloride(4.23 g (35.6 mmol)) was added dropwise into the solution in atemperature that did not exceed 25° C. Stirring was carried out at roomtemperature, and then after it had been confirmed by TLC that thestarting material had disappeared, vacuum concentration was carried out,thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine(6.25 g (yield: 99.2%)).

Reference Example 4

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in dichloromethane (40 ml), and thionyl chloride(4.23 g (35.6 mmol)) was added dropwise into the solution in atemperature that did not exceed 25° C. Stirring was carried out at roomtemperature, and then after it had been confirmed by TLC that thestarting material had disappeared, vacuum concentration was carried out,thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine(6.23 g (yield: 99.0%)).

Reference Example 5-12-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producingStep

2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200mmol)), denatured ethanol (320 ml), 2-benzimidazolethiol (30.2 g (201mmol)), and sodium hydroxide (26.8 g (670 mmol)) were added together,and reaction was carried out for approximately 2 hours at 50° C. Afterit had been confirmed by TLC that the starting material had disappeared,vacuum concentration was carried out, and ethyl acetate (430 ml) andwater (340 ml) were then added. After stirring and then leaving tostand, the aqueous layer was separated off. The organic layer was washedwith a 10% sodium hydroxide aqueous solution (110 ml), and twice withwater (110 ml), and then vacuum concentration was carried out, thusobtaining crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(69.0 g) (HPLC purity 98.7%, yield 101%).

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) was crystallized using ethyl acetate (25 ml), and thenfiltration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.80 g) (HPLC purity 99.2%, yield 96.0%).

Reference Example 5-2

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingtert-butyl(methyl) ether (30 ml), and then filtration was carried out,thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.50 g) (HPLC purity 99.2%, yield 90.0%).

Reference Example 5-3

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingdiisopropyl ether (200 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.94 g) (HPLC purity 99.1%, yield 98.8%).

Reference Example 5-4

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingtoluene (30 ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.56 g) (HPLC purity 99.1%, yield 91.2%).

Reference Example 5-5

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingacetonitrile (40 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.64 g) (HPLC purity 99.1%, yield 92.8%).

Reference Example 5-6

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingisopropyl alcohol (20 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.55 g) (HPLC purity 99.1%, yield 91.0%).

Reference Example 5-7

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingacetone (20 ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.80 g) (HPLC purity 99.2%, yield 96.0%).

Reference Example 5-8

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized usingdiethyl carbonate (90 ml), and then filtration was carried out, thusobtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (4.85 g) (HPLC purity 99.2%, yield97.0%).

Reference Example 6-1

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producingstep

2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100mmol)), denatured ethanol (160 ml), 2-benzimidazolethiol (15.0 g (100mmol)), and sodium hydroxide (13.4 g (335 mmol)) were added together,and reaction was carried out for approximately 2 hours at 50° C. Afterit had been confirmed by TLC that the starting material had disappeared,vacuum concentration was carried out, and toluene (300 ml) and water(168 ml) were then added. After stirring and then leaving to stand, theaqueous layer was separated off. The organic layer was washed with a 10%sodium hydroxide aqueous solution (50 ml), and twice with water (50 ml),and then vacuum concentration was carried out, thus obtaining crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(34.8 g) (HPLC purity 98.7%, yield 101%).

Reference Example 6-2

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized using ethylacetate (12 ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.91 g) (HPLC purity 99.3%, yield 97.0%).

Reference Example 6-3

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized usingtert-butyl(methyl) ether (12 ml), and then filtration was carried out,thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.79 g) (HPLC purity 99.2%, yield 93.0%).

Reference Example 6-4

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized usingtoluene (15 ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.84 g) (HPLC purity 99.1%, yield 94.5%).

Reference Example 6-5

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized usingacetonitrile (21 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.81 g) (HPLC purity 99.1%, yield 93.5%).

Reference Example 6-6

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized usingdiisopropyl alcohol (9 ml), and then filtration was carried out, thusobtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (2.78 g) (HPLC purity 99.4%, yield92.5%).

Reference Example 6-7

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized usingacetone (9 ml), and then filtration was carried out, thus obtaining2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (2.91 g) (HPLC purity 99.3%, yield 97.0%).

Reference Example 6-8

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized usingdiethyl carbonate (45 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.93 g) (HPLC purity 99.3%, yield 97.5%).

HPLC Conditions

Column: Inertsil ODS-2 (made by GL Science)

Mobile phase: acetonitrile:water:ammonium acetate=500:500:1

Flow speed: 0.7 ml/min

Column temperature: 35° C.

Detector: 258 nm

Reference Example 7

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 5.37 g (21.8 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using dichloromethane (14ml) and acetonitrile (92 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(6.26 g) (HPLC purity 99.7%, yield 23.9%).

Reference Example 8

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 5.37 g (21.8 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using ethyl acetate (66ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(6.15 g) (HPLC purity 99.8%, yield 23.5%).

Reference Example 9

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 7.16 g (29.1 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using dichloromethane (18ml) and acetone (120 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(8.56 g) (HPLC purity 99.7%, yield 32.7%).

Reference Example 10

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 7.16 g (29.1 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 m), vacuum concentration wascarried out, crystallization was carried out using isopropyl alcohol (88ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(8.29 g) (HPLC purity 99.7%, yield 31.7%).

Reference Example 11

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 7.16 g (29.1 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using acetonitrile (132ml), and then filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(8.25 g) (HPLC purity 99.7%, yield 31.5%).

Reference Example 12

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 8.95 g (36.4 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using acetone (165 ml), andthen filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(10.8 g) (HPLC purity 99.6%, yield 41.4%).

Reference Example 13

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 8.95 g (36.4 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into, and then extraction was carried outtwice with dichloromethane (48 ml). The dichloromethane layers werewashed twice with water (48 ml), vacuum concentration was carried out,crystallization was carried out using toluene (110 ml), and thenfiltration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(10.6 g) (HPLC purity 99.6%, yield 40.4%).

Reference Example 14

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 8.95 g (36.4 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using dichloromethane (28ml) and ethyl acetate (184 ml), and then filtration was carried out,thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(10.9 g) (HPLC purity 99.7%, yield 41.7%).

Reference Example 15

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 10.7 g (43.7 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using acetone (198 ml), andthen filtration was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(12.6 g) (HPLC purity 99.3%, yield 48.3%).

Reference Example 16

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then thesolution was cooled, and mcpba (70.2% purity; 10.7 g (43.7 mmol)) wasadded little by little such that the internal temperature did not exceed−15° C. After the addition, a 10% sodium hydroxide aqueous solution(70.8 ml) was added, the mixture was stirred and then left to stand, andthen the aqueous layer was separated off. The separated aqueous layerwas washed twice with dichloromethane (48 ml). A 2N ammonium acetateaqueous solution was then put into the solution, and then extraction wascarried out twice with dichloromethane (48 ml). The dichloromethanelayers were washed twice with water (48 ml), vacuum concentration wascarried out, crystallization was carried out using dichloromethane (27ml) and ether (220 ml), and then filtration was carried out, thusobtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(14.5 g) (HPLC purity 99.1%, yield 55.4%).

HPLC Conditions

Column: Nucleosil 5c18 (made by Chemco)

Mobile phase: methanol: phosphate buffer (pH 7)=3:2

Flow speed: 1.0 ml/min

Detector: 290 nm

Reference Example 17

Sodium hydroxide (0.557 g) was dissolved in ion exchange water (5 ml).2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(4.96 g) was then put into the solution, and after dissolution had beenconfirmed, freeze drying was carried out for 22 hours using abottle-type freeze dryer, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]1H-benzimidazolesodium salt quantitatively.

Reference Example 18

Sodium hydroxide (0.560 g) was dissolved in ion exchange water (10 ml).2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(4.98 g) was then put into solution, and after dissolution had beenconfirmed, freeze drying was carried out for 22 hours using abottle-type freeze dryer, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt quantitatively.

Reference Example 19

Sodium hydroxide (0.507 g) was dissolved in ion exchange water (15 ml).2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(4.50 g) was then put into the solution, and after dissolution had beenconfirmed, freeze drying was carried out for 22 hours using abottle-type freeze dryer, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt quantitatively.

Reference Example 20

Sodium hydroxide (0.506 g) was dissolved in ion exchange water (25 ml).2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(4.50 g) was then put into the solution, and after dissolution had beenconfirmed, freeze drying was carried out for 22 hours using abottle-type freeze dryer, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt quantitatively.

Reference Example 21

Sodium hydroxide (0.556 g) was dissolved in ion exchange water (10 ml).2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(5.00 g) was then put into the solution, and after dissolution had beenconfirmed, the solution was put into a Tray-type freeze dryer and freezedrying was carried out, thus obtaining2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt quantitatively. Here, the Tray temperature was raised to 25°C.

INDUSTRIAL APPLICABILITY

The present invention is industrial applicable, in that a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (1) that is a drug or an intermediate for theproduction of a drug can be produced through a process that does notrequire large-scale equipment and that is excellent in terms ofworkability, operability and energy conservation.

1. A process for the production of a salt precipitate represented byformula (1)

(wherein B represents an alkali metal ion), the process comprising thesteps of: dissolving a compound represented by formula (2)

in a first organic solvent and adding an alkali metal hydroxide, ordissolving the alkali metal hydroxide in the first organic solvent andadding the compound represented by formula (2); and further adding asecond organic solvent to a reaction mixture obtained.
 2. The processaccording to claim 1, wherein the first organic solvent is an alcohol.3. The process according to claim 1 or 2, wherein the first organicsolvent is methanol or ethanol.
 4. The process according to claim 1,wherein the alkali metal hydroxide is sodium hydroxide.
 5. The processaccording to claim 1, wherein the second organic solvent is an ether. 6.The process according to claim 1, wherein the second organic solvent istert-butyl(methyl) ether or diisopropyl ether.